What happens when hormone therapy fails?
If the PSA level increases while you are receiving total androgen blockade (LHRH agonist or antagonist plus androgen receptor blocker), first your doctor will stop the antiandrogen, which is called antiandrogen withdrawal (Figure 19). This causes the PSA to decrease in about 20% of patients, and the effect may last for several months to years. The LHRH analogue/antagonist therapy is continued. It is not clear why this antiandrogen withdrawal works. When the PSA rises after antiandrogen withdrawal, you may consider other forms of hormone therapy, such as ketoconazole, aminoglutethimide, estrogens, progestins, another antiandrogen, and chemotherapy.
Aminoglutethimide has produced a decrease in PSA in 48 to 80% of patients when it is given with a steroid (hydrocortisone) at the time of antiandrogen withdrawal. Side effects of aminoglutethimide include lowering of the blood pressure when you stand up (orthostatic hypotension), fatigue, gait disturbance (ataxia), and skin rash.
Ketoconazole is a medication that decreases androgen production from both the testicles and the adrenal glands and also works directly on the prostate cancer cells. In patients who have not responded to first-line hormone therapy (LHRH analogue or antagonist plus antiandrogen), Ketoconazole plus hydrocortisone decreases the PSA in about 15% of patients. In those who have not
Figure 19. Treatment of increasing PSA after primary therapy (RRPX/ interstitial seeds/EBRT).
responded to antiandrogen withdrawal, ketoconazole plus hydrocortisone decreases PSA in about 75% of men.
Ketoconazole works quickly; its effects on testosterone level start 30 minutes after it is taken, and the testosterone level is decreased by 90% within 48 hours after therapy is started. The usual dose is 200 mg three times a day for the first week and then 400 mg orally three times a day thereafter. Some men respond to a lower
Ketoconazole works quickly; its effects on testosterone level start 30 minutes after it is taken, and the testosterone level is decreased by 90% within 48 hours after therapy is started.
dose of 200 mg three times a day as long-term therapy. The recommended dose of hydrocortisone is 20 mg at breakfast and 20 mg at dinner. If you develop ankle swelling or worsening of diabetes, then the dose is decreased to 20 mg in the morning and 10 mg in the evening, or simply 10 mg twice a day.
Side effects of ketoconazole include nausea and vomiting in about 15% of patients. Ideally, it should be taken between meals and not with antacids, Carafate, hista-mine2 blockers (ranitidine [Zantac], cimetidine [Tagamet], famotidine [Pepcid], nizatidine [Axid]), or protein pump inhibitors (omeprazole [Prilosec], lansoprazole [Prevacid], Nexus). It can also increase liver function blood abnormalities but rarely causes actual liver problems. Blood should be drawn to check the liver function regularly while you are taking ketoconazole. Ketoconazole has the potential to interact with other medications that are metabolized by the liver, so check with your doctor if you are taking multiple medications to make sure that you are not taking anything that will have an interaction.
Corticosteroids (e.g., prednisone) can also decrease the production of androgens by the adrenal gland. They also have beneficial effects on appetite and energy level. Decreases in PSA have occurred in 20 to 29% of patients with hormone-refractory prostate cancer who are taking corticosteroids. Other corticosteroids, such as dexamethasone and megestrol acetate, may also improve symptoms.
Chemotherapy has an increasing role in the management of men with hormone refractory/resistant prostate cancer. Docetaxel, a chemotherapeutic drug approved for hormone refractory prostate cancer, has been shown to increase survival with manageable side effects in men with hormone refractory prostate cancer, when compared to other forms of chemotherapy. The positive response noted with docetaxel has promoted researchers to evaluate additional chemotherapeutic drugs in ongoing clinical trials. Such trials allow some patients to participate in evaluating the effectiveness and safety of newer forms of chemotherapy. They may or may not prove to be beneficial for the participant, but the information gained from them allows oncologists to learn more about prostate cancer and effective treatment options. If you are interested in clinical trials, talk to your doctor about this or contact your local cancer center.
Provenge (produced by Dendreon) is an experimental vaccine therapy for advanced prostate cancer. Provenge is developed from one's own blood. A sample of blood is withdrawn and processed to extract certain immune cells called antigen presenting cells (APCs). Protein and prostatic acid phosphatase (PHP), found in most cancers, are then mixed. The prostate acid phosphatase is fused with an immune stimulating substance called GM-CSF. The mixture is then infused back into the patient over an hour's duration. This is repeated three times over the course of a month. Recent study results have demonstrated that those patients with advanced prostate cancer who received Provenge immunotherapy lived 4 months longer than patients with advanced prostate cancer receiving placebo in the trial.